This invention relates generally to tricyclic pyridone compounds which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making such tricyclic compounds.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the consequence of HIV-1 or HIV-2 virus following its complex viral life cycle. The virion life cycle involves the virion attaching itself to the host human T-4 lymphocyte immune cell through the binding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
RNA polymerase transcribes the integrated viral DNA into viral mRNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. In most cases, without therapeutic intervention, HIV causes the host""s immune system to be debilitated, allowing opportunistic infections to set in. Without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the HIV life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treating AIDS. This transcription must occur for the virion to reproduce because the virion""s genes are encoded in RNA and the host cell transcribes only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxythymidinene (d4T), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-cytidine (3TC) have been shown to be relatively effective in certain cases in halting HIV replication at the reverse transcriptase (RT) stage.
An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs). As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.
U.S. Pat. No. 5,874,430 describes benzoxazinone non-nucleoside reverse transcriptase inhibitors for the treatment of HIV. U.S. Pat. No. 5,519,021 describe non-nucleoside reverse transcriptase inhibitors which are benzoxazinones of the formula: 
wherein X is a halogen, Z may be O.
EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula (A): 
wherein G is a variety of groups, R3 and R4 may be H, Z may be O, R2 may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R1 may be a variety of groups including substituted alkyl.
WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R3 and R4 may be H, Z may be O, R2 is substituted alkenyl or substituted alkynyl, and R1 is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(xe2x88x92)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethyn yl)-2(1H)-quinazolinone.
Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al., Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al., J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al., J. Org. Chem. 1995, 60, 1590-1594.
DE 4,320,347 illustrates quinazolinones of the formula: 
wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a given inhibitor. Thus, there is an important need to develop additional inhibitors to further combat HIV infection.
Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, including a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide novel tricyclic 2-pyridone compounds for use in therapy.
It is another object of the present invention to provide the use of novel tricyclic 2-pyridone compounds for the manufacture of a medicament for the treatment of HIV infection.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
wherein R1, R2, R8, A, W, X, Y, and Z are defined below, including any stereoisomeric form, mixtures of stereoisomeric forms, complexes, prodrug forms or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula (I): 
or a stereoisomeric form or mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof, wherein:
A is a ring selected from: 
P is O or S;
Rb, at each occurrence, is independently selected from H, F, Cl, Br, I, CN, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, C1-4 alkyl-Oxe2x80x94, or C1-4 alkyl-NHxe2x80x94, NH2;
Rc, at each occurrence, is independently selected from H, C1-4 alkyl, C1-4 alkenyl, and C1-4 alkynyl;
W is N or CR3;
X is N or CR3a;
Y is N or CR3b;
Z is N or CR3c;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
R1 is selected from the group C1-4 alkyl substituted with 0-9 halogen, cyclopropyl, hydroxymethyl, and CN;
R2 is selected from the group methyl substituted with 0-3 R3f, C1-6 alkyl substituted with 0-2 R4, C2-6haloalkyl, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, phenyl substituted with 0-2 R3d, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3d;
R3 is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, CF3, F, Cl, Br, I, xe2x80x94(CH2)tNR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94(CH2)tNHC(O)R7, xe2x80x94(CH2)tNHC(O)NR5R5a, xe2x80x94NHSO2R10, xe2x80x94Sxe2x80x94C1-4alkyl, xe2x80x94S(O)C1-4alkyl, xe2x80x94S(O)2C1-4alkyl, xe2x80x94SO2NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
R3a is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, CF3, F, Cl, Br, I, xe2x80x94(CH2)tNR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94(CH2)tNHC(O)R7, xe2x80x94(CH2)tNHC(O)NR5R5a, xe2x80x94NHSO2R10, xe2x80x94Sxe2x80x94C1-4alkyl, xe2x80x94S(O)C1-4alkyl, xe2x80x94S(O)2C1-4alkyl, xe2x80x94SO2NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3b is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a; alternatively, R3a and R3b together form xe2x80x94OCH2Oxe2x80x94;
R3c is selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R1O, and xe2x80x94SO2NR5R5a; alternatively, R3b and R3c together form xe2x80x94OCH2Oxe2x80x94;
R3d, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
R3e, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, Br, I, xe2x80x94NR5R5a, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)R6, xe2x80x94NHC(O)R7, xe2x80x94NHC(O)NR5R5a, xe2x80x94NHSO2R10, and xe2x80x94SO2NR5R5a;
R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, CN, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, OCF3, xe2x80x94O (CO)-R13, xe2x80x94OS(O)2C1-4alkyl, xe2x80x94NR12R12a, xe2x80x94C(O)R13, xe2x80x94NHC(O)R13, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, xe2x80x94NHSO2R10, and xe2x80x94SO2NR12R12a;
R4 is selected from the group H, F, Cl, Br, I, C1-6 alkyl substituted with 0-2 R3e, C3-10 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-10 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3e;
R5 and R5a are independently selected from the group H and C1-4 alkyl;
alternatively, R5 and R5a, together with the nitrogen to which they are attached, combine to form a 5-6 membered ring containing 0-10 or N atoms;
R6 is selected from the group H, OH, C1-4 alkyl, C1-4 alkoxy, and NR5R5a;
R7 is selected from the group H, C1-3 alkyl and C1-3 alkoxy;
R8 is selected from the group H, (C1-6 alkyl)carbonyl, C1-6 alkoxy, (C1-4 alkoxy)carbonyl, C6-10 aryloxy, (C6-10 aryl)oxycarbonyl, (C6-10 aryl)methylcarbonyl, (C1-4 alkyl)carbonyloxy(C1-4 alkoxy)carbonyl, C6-10 arylcarbonyloxy(C1-4 alkoxy)carbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C1-4 alkoxy)carbonyl, and NR5R5a(C1-6 alkyl)carbonyl;
R9 is selected from H, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, (C1-6 alkyl)carbonyl, C1-6 alkoxy, (C1-4 alkoxy)carbonyl, C6-10 aryloxy, (C6-10 aryl)oxycarbonyl, (C6-10 aryl)methylcarbonyl, (C1-4 alkyl)carbonyloxy(C1-4 alkoxy)carbonyl, C6-10 arylcarbonyloxy(C1-4 alkoxy)carbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C1-4 alkoxy)carbonyl, and NR5R5a (C1-6 alkyl)carbonyl;
R10 is selected from the group C1-4 alkyl and phenyl;
R11 is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with C3-6cycloalkyl substituted with 0-2 R3e, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocycle substituted with 0-2 R3e;
R12 and R12a are independently selected from H, C1-6 alkyl, C1-6 alkyl substituted with C3-6cycloalkyl substituted with 0-2 R3e, and C3-6 carbocycle substituted with 0-2 R3e;
alternatively, R12 and R12a can join to form 4-7 membered heterocyclic ring;
R13 is selected from the group H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94Oxe2x80x94C2-6 alkenyl, xe2x80x94Oxe2x80x94C2-6 alkynyl, NR12R12a, C3-6carbocycle, and xe2x80x94Oxe2x80x94C3-6 carbocycle; and
t is selected from 0 and 1.
[2] In a preferred embodiment, the present invention provides compounds of formula (I), wherein:
R2 is selected from the group methyl substituted with 0-3 R3f, C1-5 alkyl substituted with 0-2 R4, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, and phenyl substituted with 0-2 R3d, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3d, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;
R3 and R3a, at each occurrence, are independently selected from the group H, C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, NHC(O)NR5R5a, and a 5-6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group O, N, and S;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3b and R3c, at each occurrence, are independently selected from the group H, C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3a and R3b together form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from the group H, Cl, F, C1-4 alkyl substituted with 0-2 R3e, C3-6 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3e;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; and
R7 is selected from the group CH3, C2H5, CH(CH3)2, OCH3, OC2H5, and OCH(CH3)2.
[3] In another preferred embodiment, the present invention provides compounds of formula (I), wherein:
P is O;
Ring A is: 
Rb, at each occurrence, is selected from H, F, Cl, and Br, C1-4 alkyl, CN, C1-4 alkyl-NHxe2x80x94, NH2;
Rc is selected from H and methyl;
W is CR3;
X is CR3a;
Y is CR3b;
Z is CR3c;
R2 is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 0-2 R4, C2-3 alkenyl substituted with 0-2 R4, C2-3 alkynyl substituted with 0-1 R4, and C3-6 cycloalkyl substituted with 0-2 R3d;
R3, R3a, R3b, and R3c, at each occurrence, are independently selected from the group H, C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, Br, I, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3e, at each occurrence, is independently selected from the group H, C1-4 alkyl, xe2x80x94OH, C1-4 alkoxy, OCF3, F, Cl, xe2x80x94NR5R5a, xe2x80x94C(O)R6, and xe2x80x94SO2NR5R5a;
R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, CN, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94O(CO)xe2x80x94R13, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94NR12R12a;
R4 is selected from the group H, Cl, F, C1-4 alkyl substituted with 0-1 R3e, C3-5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5;
R8 is H;
R9 is H, methyl, ethyl, propyl, and i-propyl;
R11 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, and C3-6 carbocycle substituted with 0-2 R3e wherein the C3-6 carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; and
R12 and R12a are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, and C3-6 carbocycle substituted with 0-2 R3e wherein the C3-6 carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl.
[4] In another preferred embodiment, the present invention provides compounds of formula (I), wherein:
R2 is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4;
R3, R3a, R3b, and R3c, at each occurrence, are independently selected from the group H, C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, NR5R5a, NO2, xe2x80x94CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, R3 and R3a together form xe2x80x94OCH2Oxe2x80x94;
R3e, at each occurrence, is independently selected from the group CH3, xe2x80x94OH, OCH3, OCF3, F, Cl, and xe2x80x94NR5R5a;
R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, xe2x80x94OH, CN, xe2x80x94Oxe2x80x94R11, xe2x80x94O(CO)xe2x80x94R13, and xe2x80x94NR12R12a, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94OS(O)2methyl;
R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5; and
R9 is selected from H and methyl.
[5] In another preferred embodiment, the present invention provides compounds of formula (I), wherein:
R2 is selected from the group methyl substituted with 0-2 R3f, methyl substituted with 0-2 R4, ethyl substituted with 0-2 R4, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R4, and cyclopropyl substituted with 0-1 R3d;
R3e, at each occurrence, is independently selected from the group CH3, xe2x80x94OH, OCH3, OCF3, F, Cl, and xe2x80x94NR5R5a;
R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl
R5 and R5a are independently selected from the group H, CH3 and C2H5;
R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from the group CH3, C2H5, OCH3, and OC2H5;
R8 is H.
[6] In another preferred embodiment, the present invention provides compounds of formula (I), wherein:
R1 is selected from methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, CF3, CF2CH3, CN, and hydroxymethyl;
R2 is selected from the group methyl substituted with 0-2 R3f, methyl substituted with 0-2 R4, ethyl substituted with 0-2 R4, propyl substituted with 0-1 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4;
R3, R3b, and R3c are H;
R3e is CH3;
R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, CN, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94NR12R12a;
R4 is selected from the group H, cyclopropyl substituted with 0-1 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group 0, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;
R12 and R12a are independently selected from H, methyl, ethyl, propyl, and i-propyl, and C3-6 carbocycle substituted with 0-2 R3e wherein the C3-6 carbocycle is selected from cyclopropyl.
[7] Preferred compounds of the present invention are those compounds wherein the compound is of formula (Ic): 
[8] Preferred compounds of the present invention include compounds of formula (I) wherein the compound of formula (I) is selected from the compounds shown in Table 1.
7-fluoro-2-methyl-5-[(6-methyl-2-pyridinyl)methyl]-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1 (2H)-one;
5-(2-cyclopropylethynyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1 (2H)-one;
7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1 (2H)-one;
5-butyl-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(4-fluorophenylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(2-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(isopropyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(3-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(4-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(3-propynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(2-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(2-(2-pyridyl)ethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
3-chloro-7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(3-propenyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
5-(2-cyclopropylethyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(ethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
7-fluoro-5-(2-ethoxyethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;
5-Butyl-7-chloro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(2-cyclopropylethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-cyclopropylethynyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(N-cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-hydroxymethyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-3-methyl-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(2-cyclopropylethyl)-3-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(2-methoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(N-methyl-N-i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclobutylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-butylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Cyano-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Cyano-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclopropylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclopropanesulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(t-butylsulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(methylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(ethylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Fluoro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(t-butylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclopropylmethoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(cyclobutoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(Cyclobutoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(Cyclopropylmethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-3-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Cyano-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-2-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
3,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
4,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(ethoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-butyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propoxymethyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-butyl)-5-cyano-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-butyl)-5-(hydroxymethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-butyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(i-propoxymethyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(n-Butyl)-5-(1,1-difluoroethyl)-7-Fluoro-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Cyano-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
7-Chloro-5-(ethoxymethyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(allyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-methyl-1-propenyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(1-propynyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(cyanomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(ethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(dimethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(methylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-ethoxyethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(i-propylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(diethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(cyclopropylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(pentyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-butyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(vinyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(imidazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(pyrazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(1,2,4-triazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-propylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(methylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(i-propylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(pyrrolidinyl)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(3-pentanylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(dimethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(cyclopropylmethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(allylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-((R)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-((S)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(diethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
3-chloro-5-(propyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(butyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(i-propoxy)ethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-propylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(i-propoxymethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-ethoxyethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(sec-butylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(cyclopentylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(cyclobutylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(dimethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(pyrrolidinylmethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(cyclopropylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(dimethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(diethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(1,3-dioxolanyl)methyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;
5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one.
The present invention also provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compositions and methods of use comprising the compounds of the present invention include compositions and methods of use comprising the compounds of the present invention and stereoisomeric forms thereof, mixtures of stereoisomeric forms thereof, complexes thereof, crystalline forms thereof, prodrug forms thereof and pharmaceutically acceptable salt forms thereof.
In another embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula (I); and
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula (I); and
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors, HIV protease inhibitors, CCR-5 inhibitors, and fusion inhibitors.
Preferred reverse transcriptase inhibitors useful in the above method of treating HIV infection are selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, HBY1293, GW867, ACT, UC-781, UC-782, RD4-2025, MEN 10979, AG1549 (S1153), TMC-120, TMC-125, Calanolide A, and PMPA. Preferred protease inhibitors useful in the above method of treating HIV infection are selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, VX-175, MK-944, and VX-478, the CCR-5 inhibitor is selected from TAK-779 (Takeda), SC-351125 (SCH-C, Schering) and SCH-D (Schering), and the fusion inhibitor is selected from T-20 amd T1249.
In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
In a still further preferred embodiment, the reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the protease inhibitor is indinavir.
In another embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula (I); and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In another embodiment, the present invention provides novel tricyclic 2-pyridone compounds for use in therapy.
In another embodiment, the present invention provides the use of novel tricyclic 2-pyridone compounds for the manufacture of a medicament for the treatment of HIV infection.
In another embodiment, the present invention provides that Ring A is 
In another embodiment, the present invention provides that Ring A is 
In another embodiment, the present invention provides that R1 is CF3, CF2CH3, CHF2.
In another embodiment, the present invention provides that R1 is selected from the group CF3, C2F5, CF2CH3, CHF2, CH2F and cyclopropyl.
In another embodiment, the present invention provides that R1 is methyl, ethyl, propyl, i-propyl and butyl.
In another embodiment, the present invention provides that R1 is CN and hydroxymethyl.
In another embodiment, the present invention provides that R2 is selected from the group methyl substituted with 0-3 R3f, C1-5 alkyl substituted with 0-2 R4, C2-5 alkenyl substituted with 0-2 R4, C2-5 alkynyl substituted with 0-1 R4, C3-6 cycloalkyl substituted with 0-2 R3d, and phenyl substituted with 0-2 R3d, and 3-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3d, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.
In another embodiment, the present invention provides that R2 is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 0-2 R4, C2-3 alkenyl substituted with 0-2 R4, C2-3 alkynyl substituted with 0-1 R4, and C3-6 cycloalkyl substituted with 0-2 R3d.
In another embodiment, the present invention provides that R2 is selected from the group methyl substituted with 0-3 R3f, C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4.
In another embodiment, the present invention provides that R2 is selected from the group methyl substituted with 0-2 R3f, methyl substituted with 0-2 R4, ethyl substituted with 0-2 R4, propyl substituted with 0-2 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4, 2-propynyl substituted with 0-2 R4, and cyclopropyl substituted with 0-1 R3d.
In another embodiment, the present invention provides that R2 is selected from the group methyl substituted with 0-2 R3f, methyl substituted with 0-2 R4, ethyl substituted with 0-2 R4, propyl substituted with 0-1 R4, ethenyl substituted with 0-2 R4, 1-propenyl substituted with 0-2 R4, 2-propenyl substituted with 0-2 R4, ethynyl substituted with 0-2 R4, 1-propynyl substituted with 0-2 R4.
In another embodiment, R2 is selected from the group methyl substituted with 0-2 R3f, methyl substituted with 0-2 R4, and ethyl substituted with 0-2 R4.
In another embodiment, R2 is R2c.
In another embodiment, the present invention provides that R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, CN, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94O(CO)xe2x80x94R13, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94NR12R12a.
In another embodiment, the present invention provides that R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, xe2x80x94OH, CN, xe2x80x94Oxe2x80x94R11, O(CO)xe2x80x94R13, and xe2x80x94NR12R12axe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94OS(O)2methyl.
In another embodiment, the present invention provides that R3f, at each occurrence, is independently selected from the group H, F, Cl, Br, I, C1-4 alkyl, CN, xe2x80x94OH, xe2x80x94Oxe2x80x94R11, xe2x80x94SR11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, and xe2x80x94NR12R12a.
In another embodiment, the present invention provides that R4 is selected from the group H, Cl, F, C1-4 alkyl substituted with 0-2 R3e, C3-6 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-5 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-2 R3e.
In another embodiment, the present invention provides that R4 is selected from the group H, Cl, F, C1-4 alkyl substituted with 0-1 R3e, C3-5 carbocycle substituted with 0-2 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.
In another embodiment, the present invention provides that R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.
In another embodiment, the present invention provides that R4 is selected from the group H, Cl, F, CH3, CH2CH3, cyclopropyl substituted with 0-1 R3e, 1-methyl-cyclopropyl substituted with 0-1 R3e, cyclobutyl substituted with 0-1 R3e, phenyl substituted with 0-2 R3e, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted with 0-1 R3e, wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.
In another embodiment, the present invention provides that R8 is H.
In another embodiment, the present invention provides that R9 is H, methyl, ethyl, propyl, and i-propyl.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. All tautomers of shown or described compounds are also considered to be part of the present invention.
As used herein, the term xe2x80x9ctricyclic 2-pyridonesxe2x80x9d is intended to include the compounds 5,10-Dihydro-2H-benzo[b][1,7]naphthyridin-1-one which are represented by the compounds of Formula I.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The present invention is intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R4, then said group may optionally be substituted with up to two R4 groups and R4 at each occurrence is selected independently from the definition of R4. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, the following terms and expressions have the indicated meanings.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. By way of illustration, the term xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9cC1-C10 alkylxe2x80x9d is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. xe2x80x9cC1-4 alkylxe2x80x9d is intended to include C1, C2, C3, and C4 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. C2-10 alkenyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. C2-10 alkynyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. An oxo group may be a substituent on a nitrogen heteroatom to form an N-oxide. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, PMPA, and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), HBY1293 (Hoechst), GW867 (Glaxo Wellcome), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), MEN 10979 (Menarini Farmaceutici) AG1549 (S1153; Agouron), TMC-120, TMC-125, and Calanolide A.
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds that inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn), tipranavir (Pharmacia and Upjohn, U-140690), DMP-450 (DuPont), AG-1776, VX-175, MK-944, VX-478 and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Examples of prodrugs at R8 and at R9 are C16 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). 
Scheme 1 illustrates a method of preparing keto-anilines from an appropriately substituted 2-aminobenzoic acid (wherein R represents R3, R3a, R3b, and R3c). The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R1-substituted ketone. The keto-anilines are useful intermediates for the presently claimed compounds. 
Scheme 2 describes another method of preparing keto-anilines, this time from an appropriately substituted aniline. After iodination and amine protection, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides the keto-aniline. Additional means of preparing keto-anilines are known to one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814, the contents of which are hereby incorporated herein by reference. 
Another method of making 2-trifluoroacetylanilines is shown in Scheme 3. After forming the protected aniline, the amide is then reduced and the trifluoromethyl group added. Oxidation with an oxidant, such as MnO2, provides the useful intermediate. 
Scheme 4 describes a method of converting the protected aniline to the tricyclic structure. Metallation of the chloropyridine with LDA followed by condensation with the trifluoromethylketone gave the tertiary alcohol. Cyclization to the azaacridone was accomplished by heating in DMF with K2CO3 for base. After protection with SEM-Cl, the acridone was condensed with CF3TMS and Bu4NF to give the fully aromatic tricycle. Addition of nucloephiles such as cyanide and organometallics generated the quaternary addition products. Conversion of the methoxypyridine to the pyridone products was accomplished by heating with HCl or HBr.
While the above schemes describe methods of preparing the benzo analogs (i.e. wherein W, X, Y, and Z are all carbon), they can be modified by one skilled in the art to prepare the heterocyclic varieties wherein W, X, Y, or Z are equal to nitrogen. 
Scheme 5 illustrates specific steps for forming the aminoketone IIIc. Intermediate IIIb (R1a is selected from CF3, CF3CF2, and CF3CF2CF2) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF3CF2TMS, CF3CF2CF2TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x9210 to about 10xc2x0 C., more preferably about 0xc2x0 C.
Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO2, PDC, PCC, K2Cr2O7, CrO3, KMnO4, BaMNO4, Pb(OAc)4, and RuO4. A preferred oxidant is MnO2. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane. 
In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 6. This reaction is accomplished by using an anionic nucleophile of the group R1a. See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.
It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from xe2x88x9220 to +35xc2x0 C., with temperatures below 0xc2x0 C. being more preferred and xe2x88x9220xc2x0 C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent.
Patent Publications WO98/14436, WO98/45276, and WO01/29037 describe other methods of preparing the appropriately substituted anilines and are hereby incorporated by reference.
The keto-anilines can also be converted to the tricyclic compounds using procedures described in the examples.
One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.